The present invention relates in general to accelerated subcutaneous absorption, and more particularly, to a method that accelerates drug absorption rates with minimal toxicity.
By way of background and to better facilitate a complete understanding of the present invention the following terms shall have the following definitions:
Solvent: A substance (usually a liquid) having the power to dissolve other substances. In the present application, both water and commercially available crystalloids (e.g. 0.9% sodium chloride/physiologic saline or lactated Ringer's solution) are considered to be exemplary solvents.
Solute: The dissolved substance, the substance dissolved by the solvent in a solution. In the present application, preferable solutes include pharmaceutical drugs such as methyl nicotinamide, hyaluronidase, lidocaine, and epinephrine, that are dissolved in a crystalloid solvent.
Solution: The action of changing from a solid or gaseous state to a liquid state, the state of being desolved.
Tumescent Technique or Tumescent Infiltration are defined as a method of subcutaneous drug delivery of large volumes of very dilute medication together with dilute epinephrine in isotonic solution of crystalloid (e.g., physiologic saline, lactated Ringer's solution, Hartman's solutions, etc.) infiltrated directly into subcutaneous fat or muscle or along the exterior length of a vein to produce swelling and firmness, or tumescence, of the targeted tissues, and thus produce very slow systemic absorption as a result of intense subcutaneous vasoconstriction, as well as direct hydrostatic compression of capillaries and veins. Tumescent Drug Delivery, or Tumescent Delivery are synonyms that refer to the tumescent technique for delivering a drug into the subcutaneous space. In other words, tumescent delivery is a process of infiltration of very large volumes of very dilute solutions of therapeutic substances dissolved in a crystalloid solution into subcutaneous tissue to the point of producing tumescence of the targeted tissue. Drugs other than lidocaine can be administered by means of tumescent delivery, that is, by subcutaneous infiltration of extremely dilute drug, with or without a vasoconstrictor such as epinephrine.
Tumescent and tumescence are synonyms for swollen and firm.
Tumescent liposuction is defined as liposuction performed totally by local anesthesia using tumescent local anesthesia.
Tumescent fluid and/or tumescent solution are defined as dilute solutions of therapeutic substances dissolved in a crystalloid solution intended for tumescent delivery into subcutaneous tissue.
Tumescent “drug”: the “drug” in the context as an ingredient in a tumescent solution and its pharmacokinetic behavior as a result of the pharmacokinetics of a tumescent solution; for example tumescent lidocaine, tumescent epinephrine, tumescent antiobiotic.
Tumescent Local Anesthesia (TLA) is local anesthesia produced by direct infiltrations into subcutaneous tissues of large volumes of very dilute lidocaine (e.g., less than or equal to 1 gram/liter) and epinephrine (e.g., less than or equal to 1 milligram/liter) with sodium bicarbonate (e.g., 10 milliequivalents/liter) in a crystalloid solution such as physiologic saline (NaCl) or lactated Ringer's solution. Although higher concentrations can be used and still qualify as TLA, it is generally safer to use the least (lowest) effective concentration.
Tumescent Local Anesthetic Solution (TLA Solution) is the local anesthetic solution used to produce TLA. Typically, a TLA Solution consists of a 10 to 20 fold dilution of commercially available concentration of lidocaine and epinephrine. Thus, a commercial solution of lidocaine and epinephrine contains 10 grams of lidocaine per liter (10 gm/L) and 10 milligrams of epinephrine per liter. In contrast TLA Solution typically contains very dilute lidocaine (≦1 gram/liter) and epinephrine (≦1 milligram/liter) with sodium biocarbonate (10 milliequivalents/liter) in a crystalloid solution such as physiologic saline or lactated Ringer's solution. Typically the volume of infiltrated TLA Solution is so large that the skin and subcutaneous tissue becomes tumescent, in other words swollen and firm.
Tumescent Pharmacokinetics is defined as the absorption pharmacokinetics [the pharmacologic and physiologic factors associated with the systemic absorption of a drug] after tumescent infiltration of a drug is dramatically slower than the rate of systemic absorption of routine injection of the drug. The intense vasoconstriction induced by epinephrine, slows the rate of drug absorption into the central circulation and prolongs the local effects of the drug. For example, the duration of local anesthesia with lidocaine is typically 2 hours, in contrast the duration of local anesthesia with tumescent local anesthesia is 12 to 18 hours or more. A similar prolonged effect of tumescent antibiotic infiltration significantly improves the prophylactic effect of preoperative antibiotic therapy in the prevention of surgical site infections.
Bulk flow: The physical flow of a volume of fluid through a space, for example, water flowing through a sieve or strainer. Water flowing through the interstitial space between cells of a tissue is one example of the phenomenon of bulk flow in physiology.
In clinical situations such as severe trauma, hypoglycemia or dehydration which requires an immediate systemic administration of fluids or drugs, the most effective mode of delivery is often an intravenous (IV) infusion. However, IV infusion is not always easily accomplished or possible, in particular when the veins of a patient are difficult to locate due to severe dehydration or when ambient light is so low that the veins of the patient are not visible. Further, substantial clinical skills are typically required for gaining IV access. Therefore, during an emergency situation in isolated areas far from trained medical clinicians, IV administration of drugs may not be possible. As such, often times patients must wait until trained clinicians and proper facilities are available to insert and establish secure IV access. However any significant delay in establishing an IV site and administrating required drugs can have serious adverse consequences. Thus, there exists a substantial need in the art for a simple, safe technique that can be performed by a layman and which produces a rapid systemic administration of a drug or a fluid applied to a patient by subcutaneous infiltration or topical application.
Although not by way of limitation, the present invention is specifically suited for use with Applicant's Infiltration Cannula disclosed in pending U.S. patent application Ser. No. 10/877,566, filed Jun. 25, 2004 entitled INFILTRATION CANNULA, the disclosure of which is expressly incorporated herein by reference as disclosed therein A suitable Infiltration Cannula consists of a flexible plastic cannula (approximately 15 to 20 cm long) with holes (apertures) arranged along the distal 90% of the flexible cannula, and through which tumescent fluid can be rapidly delivered to subcutaneous tissue or muscle. Known as Kleinfiltrator™ cannulas, these flexible infiltration cannulas provide a means for relatively rapid fluid resuscitation in emergency situations when establishing an intravenous (IV) access is not feasible. These flexible infiltration cannulas have important applications in treating wounded soldiers in night-time combat conditions when establishing an IV access in total darkness is nearly impossible without using a flash light, and using a flash light might attract deadly enemy fire. Such flexible infiltration cannulas also have important applications in treating mass-casualty victims suffering hypovolemia as a result of epidemic infections, biologic warfare, or trauma such as explosions, burns or radiation exposure. Such flexible infiltration cannulas also have applications in surgical patients wherein the surgeon can provide localized preoperative preemptive analgesia and simultaneously provide tumescent delivery of a prophylactic dose of an antibiotic aimed precisely at tissues targeted for surgical intervention.
The present invention comprises a method of accelerated subcutaneous absorption, which is intended to act in concert with such flexible infiltration cannula or other suitable infiltration cannula. Such infiltration cannulas allow rapid tumescent infiltration of a large volume of crystalloid solution (possibly containing additional therapeutic drugs) into subcutaneous tissue or muscle. The method of accelerated systemic absorption of fluid then provides a means of maximizing the delivery of the tumescent solution to the systemic circulation.